Process for the directed fluoralkylation synthesis of 2-methyl-4-heptafluoroisopropyl aniline

Abstract

This invention discloses a process for the directional fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline, relating to the field of directional organic compound synthesis technology. The process is as follows: a p-bromotoluene solution is prepared and introduced into a titration channel at low temperature for titration with a nitrated mixed acid; 2-nitro-4-bromotoluene is dissolved in methanol and introduced into a mixed flow channel, along with a saturated ammonium formate solution and a catalyst solution; 2-nitrotoluene is dissolved in methanol and introduced into a gas-filled channel, into which hydrogen gas and the catalyst solution are introduced; acetic anhydride is added dropwise to the reaction solution in an acetylation channel; N-acetyl-2-methyl-4-heptafluoroisopropylaniline is prepared using heptafluoroisopropyl iodine; the product is added to 37% concentrated hydrochloric acid, along with an appropriate amount of methanol solution, and refluxed at 100-105°C. This invention solves the problems of high raw material cost, low purity, difficult purification, and high energy consumption in existing preparation methods.

Description

Technical Field

[0001] This invention belongs to the field of directed synthesis of organic compounds, and in particular relates to a process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline. Background Technology

[0002] The existing process for synthesizing 2-methyl-4-heptafluoroisopropylaniline by directed fluoroalkylation involves radical fluoroalkylation of o-toluidine with 2-bromoheptafluoropropane (phase transfer catalysis / pressurization). However, o-toluidine is expensive to purchase from the market, and the o-toluidine produced by nitration of methylbenzene with nitrated mixed acid has low purity. This application provides a new route for the preparation of o-toluidine.

[0003] In the process of preparing and synthesizing 2-methyl-4-heptafluoroisopropylaniline, each step is a tank reaction. When purifying the product, the reaction solution needs to be extracted after the reaction is completed for purification. It is impossible to achieve continuous reaction and real-time production of product reaction solution. The intermittent process leads to high equipment energy consumption. Summary of the Invention

[0004] The purpose of this invention is to provide a process for the directional fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline, which achieves continuous production of o-toluidine through a titration channel and a mixed flow channel, and uses a new process to prepare relatively pure o-toluidine, thereby reducing the cost of o-toluidine and solving the problems of high raw material cost, low purity, difficult purification, and high energy consumption in existing preparations.

[0005] To solve the above-mentioned technical problems, the present invention is achieved through the following technical solution:

[0006] This invention discloses a process for the directional fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline, the specific process steps of which are as follows:

[0007] S1: Dissolve p-bromotoluene in dichloromethane to prepare a 1.0-1.5 mol / L p-bromotoluene solution, refrigerate at 0-10℃ for later use, drain the p-bromotoluene solution into the titration channel at low temperature and titrate with nitrated mixed acid, and wash the reaction solution with water, evaporate light under reduced pressure, and recrystallize with ethanol to obtain 2-nitro-4-bromotoluene;

[0008] S2: Dissolve 2-nitro-4-bromotoluene from step S1 in methanol solution and discharge it into a mixed flow channel. Then, pass a saturated ammonium formate solution and mix in 10% Pd / C solution. React in the mixed flow channel for 1-3 hours at a reaction temperature of 65-70℃. The reaction solution is then subjected to hot filtration, rotary evaporation, extraction and vacuum distillation to obtain 2-nitrotoluene.

[0009] S3: Dissolve 2-nitrotoluene from step S2 in methanol solution and discharge it into the gas filling channel. Discharge hydrogen gas and 10% Pd / C solution into the gas filling channel. After the reaction is completed, discharge the reaction solution into the acetylation channel.

[0010] S4: Acetic anhydride is added dropwise to the initial end of the reaction solution in step S3, and the reaction is allowed to proceed within the acetylation channel for 1-2 hours. After precipitation with ice water, filtration and washing with water, and recrystallization with ethanol / water, pure N-acetyl-o-toluidine is obtained.

[0011] S5: Dissolve N-acetyl-o-toluidine from step S4 in a solvent, add tetrabutylammonium bromide to dissolve, place in a directional reaction vessel and add heptafluoroisopropyl iodine, remove oxygen by nitrogen purging, then add water and sodium bicarbonate, and finally add sodium thiosulfate dropwise in batches. The reaction is carried out under nitrogen protection for 4-8 hours. After washing with water to remove salt, remove iodine to decolorize and recrystallize, N-acetyl-2-methyl-4-heptafluoroisopropylaniline is obtained.

[0012] S6: N-acetyl-2-methyl-4-heptafluoroisopropylaniline was added to 37% concentrated hydrochloric acid and an appropriate amount of methanol solution was added. The mixture was refluxed at 100-105℃ for 4-8 hours and purified to obtain 2-methyl-4-heptafluoroisopropylaniline.

[0013] The present invention is further configured such that the titration channel includes multiple titration flow pipes and multiple temporary reaction cylinders, the output end of the first titration flow pipe is connected to the side wall of the first temporary reaction cylinder near the top, the input end of the second titration flow pipe is connected to the bottom of the first temporary reaction cylinder, and the output end is connected to the side wall of the second temporary reaction cylinder near the top, thereby connecting 3-5 titration flow pipes and temporary reaction cylinders in sequence;

[0014] The nitrated mixed acid comprises 65% nitric acid and 98% sulfuric acid. A titration port for the nitrated mixed acid is set at the initial end of each titration flow pipe. The proportion of nitric acid in the nitrated mixed acid titrated from the first titration flow pipe to each subsequent titration flow pipe decreases step by step. The ratio of 65% nitric acid and 98% sulfuric acid titrated at the position of the first titration flow pipe is 1:4-5.

[0015] The present invention is further configured such that the reaction liquid in the last temporary reaction cylinder flows into the washing tank and cold water is simultaneously discharged into the washing tank for washing. When the washing tank is almost full, no more liquid is discharged. After standing still, the lower organic phase is discharged, and the reaction liquid in the last temporary reaction cylinder will flow into the next washing tank for washing. This process is repeated continuously.

[0016] The discharged organic phase is discharged into an organic phase washing tank. 5% NaHCO3 is added to the organic phase washing tank to wash until it is weakly alkaline / neutral. It is then washed once with saturated brine to separate the lower organic phase. The organic phase is then dried with anhydrous Na2SO4 and filtered to obtain anhydrous organic phase.

[0017] The present invention is further configured such that the mixing channel includes multiple square mixing channels, an exhaust pipe and a condenser return pipe, the multiple square mixing channels are connected sequentially and set down step by step, each square mixing channel has an upward exhaust pipe at the top of the output end, the exhaust end of the exhaust pipe is connected to the bottom side wall of the condenser pipe, and the bottom return pipe of the condenser pipe is inserted downward into the input end of the next square mixing channel;

[0018] After the 2-nitro-4-bromotoluene solution is discharged, the ammonium formate solution is introduced by inflow or by multiple dropper heads, and a Pd / C solution dropper is set at a distance behind the ammonium formate solution dropper position.

[0019] The present invention is further configured such that the inflation channel includes multiple thick cylinders and multiple Z-shaped pipes, each of the thick cylinders is placed horizontally, and each of the thick cylinders has an inlet and an outlet near the bottom and top, respectively. The multiple thick cylinders are connected by a Z-shaped pipe and the outlet at the top of the previous thick cylinder is connected to the inlet at the bottom of the next thick cylinder.

[0020] Each of the Z-shaped pipes is equipped with a hydrogen branch pipe near the liquid inlet. The hydrogen branch pipe is used to discharge hydrogen into the Z-shaped pipe. The amount of hydrogen discharged into the Z-shaped pipe from the first to the last branch pipe decreases step by step.

[0021] The first coarse cylinder has a catalyst connector on the reaction liquid drain pipe connected to the inlet. The Pd / C solution is discharged into the first coarse cylinder through the catalyst connector. The reaction liquid drain pipe is also equipped with an initial hydrogen branch pipe.

[0022] The present invention is further configured such that the acetylation channel comprises multiple acylated square tubes arranged in a descending manner, each of the acylated square tubes having an inlet and an outlet at the two ends near the top and bottom, respectively, and adjacent acylated square tubes are connected by a pipe to the outlet and inlet.

[0023] Each section of the acylated square tube has an acetic anhydride burette at the top near the inlet.

[0024] The present invention is further configured such that in step S4, each step of ice-water precipitation, filtration and washing, and ethanol / water recrystallization requires the setting of multiple parallel processing tanks, so as to ensure that when the reaction liquid continuously discharged from the acetylation channel enters the ice-water precipitation processing tank, the reaction liquid in one tank can be transferred to another empty tank in a timely manner when the reaction liquid in one tank is full.

[0025] The present invention is further configured such that the number of directional reaction tanks matches the number of parallel processing tanks, that is, the raw materials after recrystallization of ethanol / water in one tank are discharged into one directional reaction tank for directional reaction;

[0026] Step S5, water washing for desalination, iodine removal and decolorization, and recrystallization, are also multiple parallel operations. The reaction solution after the reaction in each of the directional reaction tanks is subjected to water washing for desalination, iodine removal and decolorization, and recrystallization once.

[0027] The present invention is further configured such that, in step S6, multiple deacylation reaction reflux tanks are configured, and the N-acetyl-2-methyl-4-heptafluoroisopropylaniline produced after the reaction solution of each of the directional reaction tanks is washed with water to remove salt, remove iodine to remove color and recrystallize is added to a deacylation reaction reflux tank for reaction;

[0028] The purification of the reaction solution after each deacylation reaction in the reflux tank is an independent step, and the purification steps are as follows: 1. Alkalize the reaction solution to pH 9-10 with concentrated ammonia / 50% NaOH, and slowly add it under ice bath; 2. Extract twice with dichloromethane / ethyl acetate; 3. Wash once with saturated brine; 4. Dry with anhydrous Na2SO4 and filter; 5. Rotary evaporation and vacuum distillation.

[0029] The present invention has the following beneficial effects:

[0030] 1. This invention uses p-bromotoluene as the initial raw material and achieves continuous production through titration channels, mixed flow channels, and gas-filling channels. The production process yields high-purity products with low purification requirements. After preparation, the o-toluidine product undergoes direct acetylation followed by heptafluoroisopropyl-directed synthesis of N-acetyl-2-methyl-4-heptafluoroisopropylaniline, achieving extremely high purity, even higher than that obtained by free radical fluoroalkylation of o-toluidine with 2-bromoheptafluoropropane. Most importantly, the o-toluidine raw material is not purchased from the market but is produced continuously, eliminating the need for storage before proceeding to the next reaction. This addresses the issue that commercially available o-toluidine requires excellent storage conditions and cannot be stored for extended periods. This invention enables the production of only the amount of o-toluidine raw material needed, allowing for timely processing of the o-toluidine raw material preparation product without storage. It also prevents the o-toluidine raw material from becoming ineffective or deteriorating due to improper storage or prolonged storage. The easy storage of p-bromotoluene significantly reduces raw material storage costs.

[0031] 2. The directional reaction of this invention is based on the continuous production of o-toluidine. Since o-toluidine is produced continuously, the subsequent preparation of N-acetyl-o-toluidine and heptafluoroisopropyl iodine is also carried out continuously. Multiple tanks are arranged side by side, with one tank being filled and another being filled. This is all due to the continuous production of o-toluidine, which greatly improves the utilization rate of raw materials and production efficiency.

[0032] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description

[0033] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1 This is a schematic diagram illustrating the principle of a directed fluoroalkylation process for synthesizing 2-methyl-4-heptafluoroisopropylaniline.

[0035] Figure 2 This is a schematic diagram of the titration channel.

[0036] Figure 3 This is a schematic diagram of the mixed-flow channel.

[0037] Figure 4 This is a schematic diagram of the inflation channel.

[0038] The attached diagram lists the components represented by each number as follows:

[0039] 1. Titration flow channel; 11. Titration port for nitrated mixed acid; 2. Temporary reaction chamber; 3. Square mixing channel; 31. Dropper head; 32. Pd / C solution dropper; 33. Exhaust pipe; 4. Condenser; 41. Reflux pipe; 5. Coarse cylinder; 6. Reaction liquid drain pipe; 61. Catalyst inlet pipe; 62. Initial hydrogen branch pipe; 7. Z-shaped pipe; 71. Hydrogen branch pipe. Detailed Implementation

[0040] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Please see Figures 1-4 This invention discloses a process for the directional fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline, the specific process steps of which are as follows:

[0042] S1: Dissolve p-bromotoluene in dichloromethane to prepare a 1.0-1.5 mol / L p-bromotoluene solution, refrigerate at 0-10℃ for later use, drain the p-bromotoluene solution into titration channel 001 at low temperature and titrate with nitrated mixed acid, and wash the reaction solution with water, evaporate light under reduced pressure, and recrystallize with ethanol to obtain 2-nitro-4-bromotoluene.

[0043] S2: Dissolve 2-nitro-4-bromotoluene from step S1 in methanol solution and discharge it into mixed flow channel 002. Then, pass saturated ammonium formate solution and mix in 10% Pd / C solution. React in mixed flow channel 002 for 1-3 hours at a reaction temperature of 65-70℃. The reaction solution is then subjected to hot filtration, rotary evaporation, extraction and vacuum distillation to obtain 2-nitrotoluene.

[0044] S3: Dissolve 2-nitrotoluene from step S2 in methanol solution and discharge it into gas filling channel 003. Discharge hydrogen gas and 10% Pd / C solution into gas filling channel 003. After the reaction is completed, discharge the reaction solution into acetylation channel.

[0045] S4: Acetic anhydride is added dropwise to the initial end of the reaction solution in step S3, and the reaction is allowed to proceed within the acetylation channel for 1-2 hours. After precipitation with ice water, filtration and washing with water, and recrystallization with ethanol / water, pure N-acetyl-o-toluidine is obtained.

[0046] S5: Dissolve N-acetyl-o-toluidine from step S4 in a solvent, add tetrabutylammonium bromide to dissolve, place in a directional reaction vessel and add heptafluoroisopropyl iodine, remove oxygen by nitrogen purging, then add water and sodium bicarbonate, and finally add sodium thiosulfate dropwise in batches. The reaction is carried out under nitrogen protection for 4-8 hours. After washing with water to remove salt, remove iodine to decolorize and recrystallize, N-acetyl-2-methyl-4-heptafluoroisopropylaniline is obtained.

[0047] S6: N-acetyl-2-methyl-4-heptafluoroisopropylaniline was added to 37% concentrated hydrochloric acid and an appropriate amount of methanol solution was added. The mixture was refluxed at 100-105℃ for 4-8 hours and purified to obtain 2-methyl-4-heptafluoroisopropylaniline.

[0048] Purchasing p-bromotoluene, which is very easy to store (bulk purchases are cheaper and lower in cost), prepares a p-bromotoluene solution for refrigeration and storage. The solution is then pumped into titration channel 001 at a constant rate using a liquid pump. Titration channel 001 allows for continuous delivery of the p-bromotoluene solution, ensuring that the nitrated mixed acid reacts fully. Since the p-bromotoluene solution is mainly 2-nitro-4-bromo-toluene after nitration, its purity is much higher than that of toluene directly reacting with the nitrated mixed acid.

[0049] 2-Nitro-4-bromotoluene reacts with a saturated ammonium formate solution in a mixed-flow channel 002, and a 10% Pd / C catalyst solution is added dropwise to remove bromine. High-purity 2-nitrotoluene is obtained through hot filtration, rotary evaporation, extraction, and vacuum distillation. The reaction solution itself is at 65-70℃, allowing for direct hot filtration. The solution flows onto a filter screen to remove catalyst particles before proceeding with subsequent purification processes.

[0050] To accommodate continuous production, a gas-filled channel 003 is configured. 2-Nitrotoluene is dissolved in methanol solution, and the reaction occurs continuously in channel 003, resulting in a continuous output of products, eliminating the need for batch-by-batch reaction preparation. This method ensures high hydrogen utilization and a complete and thorough reaction.

[0051] The reaction solution (o-toluidine) in step S3 does not require purification and proceeds directly to the next reaction for acetylation. The purpose of acetylation is to acetylate the amino group and further passivate the ortho-position (6-carbon). This results in the formation of N-acetyl-2-methyl-4-heptafluoroisopropylaniline with almost 100% purity. After purification and deacetylation, a higher concentration of 2-methyl-4-heptafluoroisopropylaniline can be obtained, and the directional reaction is more precise.

[0052] The titration channel 001 includes multiple titration flow pipes 1 and multiple temporary reaction cylinders 2. The output end of the first titration flow pipe 1 is connected to the side wall of the first temporary reaction cylinder 2 near the top. The input end of the second titration flow pipe 1 is connected to the bottom of the first temporary reaction cylinder 2, and the output end is connected to the side wall of the second temporary reaction cylinder 2 near the top. In this way, 3-5 titration flow pipes 1 and temporary reaction cylinders 2 are connected in sequence.

[0053] The nitrated mixed acid includes 65% nitric acid and 98% sulfuric acid. A titration port 11 for the nitrated mixed acid is provided at the initial end of each titration flow pipe 1. The proportion of nitric acid in the nitrated mixed acid titrated from the first titration flow pipe 1 to each subsequent titration flow pipe 1 decreases step by step. The ratio of 65% nitric acid and 98% sulfuric acid titrated at the position of the first titration flow pipe 1 is 1:4-5.

[0054] like Figure 2During the titration process, sulfuric acid increases due to the consumption of nitric acid. However, the p-bromotoluene solution flows into the first titration flow channel at a near-uniform rate. A nitrifying mixed acid titration port 11 is set at the initial position of the top of the cap, and the nitrifying mixed acid is added dropwise (the amount added is insufficient for complete reaction). This ensures that the nitric acid achieves a significant nitration. After the first titration, the solution flows into the first temporary reaction chamber 2, allowing the nitric acid to react fully and ensuring thorough mixing of the sulfuric acid and p-bromotoluene solution. The solution then flows out from the bottom of the temporary reaction chamber 2 and enters the initial position of the second titration flow channel 1 for a second titration. During the second titration, the acid quantity is reduced, and the nitric acid ratio is also reduced. This is because the p-bromotoluene concentration decreases after the first titration, and since the solution contains sulfuric acid, the instantaneous concentration of the nitrifying mixed acid upon addition will definitely be higher than before. Reducing the nitric acid ratio is more conducive to the formation of only a mononitro product. The nitrifying mixed acid ratio is gradually reduced in subsequent titrations because the p-bromotoluene concentration is lower, requiring less nitric acid, and the titration quantity also needs to be reduced in subsequent titrations. The following are examples of mixing ratios for 65% nitric acid and 98% sulfuric acid: 1:5-7, 1:7-10, 1:10-12, etc., with the ratio decreasing step by step.

[0055] Titration allows for the full utilization of nitric acid and ensures a complete reaction.

[0056] The reaction liquid in the last temporary reaction tank 2 flows into the washing tank, and cold water is simultaneously discharged into the washing tank for washing. When the washing tank is almost full, no more liquid is discharged. After standing still, the lower organic phase is discharged, and the reaction liquid in the last temporary reaction tank 2 will flow into the next washing tank for washing. This process of continuous washing is carried out.

[0057] The discharged organic phase is discharged into an organic phase washing tank. 5% NaHCO3 is added to the organic phase washing tank to wash until it is weakly alkaline / neutral. It is then washed once with saturated brine to separate the lower organic phase. The organic phase is then dried with anhydrous Na2SO4 and filtered to obtain anhydrous organic phase.

[0058] The product of the reaction with p-bromotoluene is 2-nitro-4-bromotoluene. The water washing is a flowing water wash, in which the reaction solution is continuously fed into the washing tank while cold water is simultaneously added to the tank for mixing. When the tank is almost full, the addition of reaction solution and cold water is stopped, and the mixture is immediately transferred to another washing tank for further washing. After the washing tank is full, it is allowed to stand for a while, allowing the organic phase to settle. Then, the drain pipe at the bottom of the washing tank is connected to the organic phase washing tank (the upper layer is discharged from another drain pipe, mainly sulfuric acid and a very small amount of nitric acid solution). 5% NaHCO3 is added to the tank to thoroughly wash away the strong acids (sulfuric acid and nitric acid) remaining in the organic phase, preventing the product from being damaged, discolored, or decomposed by acid during subsequent heating.

[0059] The product is washed again with saturated brine to dehydrate, break the emulsion, and reduce product loss. The lower layer is the organic phase.

[0060] Finally, the organic phase was dried with anhydrous Na2SO4 to remove the small amount of water contained in the organic phase, and then filtered to obtain the organic phase.

[0061] Thorough water washing is crucial for subsequent purification. Afterward, vacuum distillation and ethanol recrystallization are performed. Small amounts of low-boiling-point byproducts and light component impurities from organic solvents (such as dichloromethane, ethyl acetate, and toluene) are evaporated by vacuum distillation, and the reflux yields a relatively pure product. However, the purity is only 90-95%, and further ethanol recrystallization is required to obtain a relatively pure 2-nitro-4-bromotoluene.

[0062] The mixing channel 002 includes multiple square mixing channels 3, an exhaust pipe 33, and a condenser return pipe 4. The multiple square mixing channels 3 are connected sequentially and set down step by step. Each square mixing channel 3 has an upward exhaust pipe 33 at the top of the output end. The exhaust end of the exhaust pipe 33 is connected to the bottom side wall of the condenser pipe. The bottom return pipe 41 of the condenser pipe 4 is inserted downward into the input end of the next square mixing channel 3.

[0063] After the 2-nitro-4-bromotoluene solution is discharged, the ammonium formate solution is added by inflow or by multiple dropper heads 31, and a Pd / C solution dropper 32 is set at a distance behind the ammonium formate solution dropper position.

[0064] The removal of bromine requires a saturated ammonium formate solution. Combined with a 10% Pd / C catalyst solution, the reaction is more complete. During the reaction, ammonia and carbon dioxide gases are produced, mixed with methanol volatiles (65-70℃). This mixed gas, passing through exhaust pipe 33, flows upwards into condenser reflux pipe 4 (condenser). Since methanol condenses into liquid, it flows downwards into reflux pipe 41 and into the next square mixing channel 3, redistributing the 2-nitrotoluene solution (achieving methanol reflux). This process of adding ammonium formate solution and reacting repeatedly gradually decreases the 2-nitro-4-bromotoluene content while increasing the concentration of 2-nitro-toluene until it is completely converted to 2-nitro-toluene. However, a byproduct, 2-aminotoluene (o-toluidine), is generated. This is not a problem, as o-toluidine is desired later, so an additional gas-filling channel 003 reaction step is added. The condenser reflux pipe 4 serves to promptly remove impurities (ammonia and carbon dioxide).

[0065] The inflation channel 003 includes multiple thick cylinders 5 and multiple Z-shaped pipes 7. Each thick cylinder 5 is placed horizontally. The two ends of the thick cylinder 5 are respectively provided with an inlet and an outlet near the bottom and the top. The multiple thick cylinders 5 are connected by a Z-shaped pipe 7 and the outlet at the top of the previous thick cylinder 5 is connected to the inlet at the bottom of the next thick cylinder 5.

[0066] Each of the Z-shaped pipes 7 is provided with a hydrogen branch pipe 71 near the liquid inlet. The hydrogen branch pipe 71 is used to discharge hydrogen into the Z-shaped pipe 7. The amount of hydrogen discharged into the Z-shaped pipe 7 by the hydrogen branch pipe 71 decreases step by step from the first to the last.

[0067] The first coarse cylinder 5 is equipped with a catalyst connector 61 on the reaction liquid drain pipe 6 connected to the liquid inlet. The Pd / C solution is discharged into the first coarse cylinder 5 through the catalyst connector 61. The reaction liquid drain pipe 6 is also equipped with an initial hydrogen branch pipe 62.

[0068] like Figure 4 The inlet of the coarse cylinder 5 is located near the bottom. Due to the discharge, flowing liquid rushes into the coarse cylinder 5, forming a vortex. Hydrogen gas forms small bubbles that float in the coarse cylinder 5. Some unreacted bubbles will float to the top of the coarse cylinder 5 and reach the outlet. The bubbles will converge with the reaction liquid at the outlet. Some bubbles will float and mix with the reaction liquid and enter the Z-shaped pipe 7 to increase the degree of reaction. Then, hydrogen gas is appropriately added at the hydrogen branch pipe 71 of the Z-shaped pipe 7 to further carry out the reaction. In this way, after passing through multiple coarse cylinders 5, the nitro group will be basically reduced, and finally o-toluidine will be formed.

[0069] The acetylation channel comprises multiple acylated square tubes arranged in a descending sequence. Each acylated square tube has an inlet and an outlet near the top and bottom, respectively. Adjacent acylated square tubes are connected by pipes to the outlet and inlet.

[0070] Each section of the acylated square tube has an acetic anhydride burette at the top near the inlet.

[0071] The structure of the acetylation channel is similar to that of the titration channel 001, except that there is no temporary reaction chamber 2. Since the reaction requires an optimal temperature of 0-5°C, the acetylation channel needs to be cooled. Titration of acetic anhydride at low temperatures does not require a catalyst, and the reaction is fast and complete.

[0072] The subsequent ice-water precipitation, filtration and washing, and ethanol / water recrystallization are similar to the purification process in step S1, and the principles are similar. They mainly involve purifying the organic phase and dehydration, so they will not be described in detail again and are considered routine techniques.

[0073] In step S4, multiple parallel processing tanks are required for each step, including ice-water precipitation, filtration and washing, and ethanol / water recrystallization. This ensures that when the reaction solution continuously discharged from the acetylation channel enters the ice-water precipitation tank, the reaction solution in one tank can be transferred to another empty tank in a timely manner when the reaction solution in one tank is full.

[0074] However, multiple tanks are needed for each step of ice water precipitation, filtration and washing, and ethanol / water recrystallization because the reaction products are continuously output. By using tanks arranged side by side, the continuously output reaction liquid can be continuously processed. In this way, the purified N-acetyl-o-toluidine comes out one tank at a time, which is equivalent to continuous production.

[0075] The number of directional reaction tanks is matched with the number of parallel processing tanks, that is, the raw materials after recrystallization of ethanol / water in one tank are discharged into one directional reaction tank for directional reaction.

[0076] Step S5, water washing for desalination, iodine removal and decolorization, and recrystallization, are also multiple parallel operations. The reaction solution after the reaction in each of the directional reaction tanks is subjected to water washing for desalination, iodine removal and decolorization, and recrystallization once.

[0077] The directional reaction vessel is mainly used for the directional reaction of heptafluoroisopropyl iodine to form heptafluoroisopropyl. Since N-acetyl-o-toluidine is produced one vessel at a time, the next directional reaction can be carried out immediately after each vessel is produced.

[0078] Step S6 involves configuring multiple deacylation reaction reflux tanks. The N-acetyl-2-methyl-4-heptafluoroisopropylaniline produced after the reaction solution in each of the directional reaction tanks is washed with water to remove salt, remove iodine, decolorize, and recrystallize is added to a deacylation reaction reflux tank for reaction.

[0079] The purification of the reaction solution after each deacylation reaction in the reflux tank is an independent step, and the purification steps are as follows: 1. Alkalize the reaction solution to pH 9-10 with concentrated ammonia / 50% NaOH, and slowly add it under ice bath; 2. Extract twice with dichloromethane / ethyl acetate; 3. Wash once with saturated brine; 4. Dry with anhydrous Na2SO4 and filter; 5. Rotary evaporation and vacuum distillation.

[0080] Finally, deacetylation is required, which also involves a batch reaction, as the directional reaction tanks also operate on a batch-by-batch basis.

[0081] The detailed steps of purifying the reaction solution after the deacylation reaction reflux tank reaction will not be repeated here, as they are standard techniques. Only the key technical points and methods of the steps will be described. The reasons for separating the organic phase, dehydration, and distillation have been explained earlier, and the same applies here, except that the conditions must meet the purification requirements of the reaction solution after the deacylation reaction reflux tank reaction.

[0082] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0083] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline, characterized in that: The specific process steps are as follows: S1: Dissolve p-bromotoluene in dichloromethane to prepare a 1.0-1.5 mol / L p-bromotoluene solution, store it at 0-10℃ for later use, and then discharge the p-bromotoluene solution into the titration channel (001) at low temperature for titration reaction with nitrated mixed acid. After washing with water, distilling light under reduced pressure, and recrystallizing with ethanol, 2-nitro-4-bromotoluene is obtained. S2: Dissolve 2-nitro-4-bromotoluene from step S1 in methanol solution and discharge it into the mixed flow channel (002), and pass in saturated ammonium formate solution and 10% Pd / C solution. React in the mixed flow channel (002) for 1-3 hours at a reaction temperature of 65-70℃. The reaction solution is then subjected to hot filtration, rotary evaporation, extraction and vacuum distillation to obtain 2-nitrotoluene. S3: Dissolve 2-nitrotoluene from step S2 in methanol solution and discharge it into the gas filling channel (003). Discharge hydrogen gas and 10% Pd / C solution into the gas filling channel (003). After the reaction is completed, discharge the reaction solution into the acetylation channel. S4: Acetic anhydride is added dropwise to the initial end of the reaction solution in step S3, and the reaction is allowed to proceed within the acetylation channel for 1-2 hours. After precipitation with ice water, filtration and washing with water, and recrystallization with ethanol / water, pure N-acetylatedotoluidine is obtained. S5: Dissolve N-acetyl-o-toluidine from step S4 in a solvent, add tetrabutylammonium bromide to dissolve, place in a directional reaction vessel and add heptafluoroisopropyl iodine, remove oxygen by nitrogen purging, then add water and sodium bicarbonate, and finally add sodium thiosulfate dropwise in batches. The reaction is carried out under nitrogen protection for 4-8 hours. After washing with water to remove salt, remove iodine to decolorize and recrystallize, N-acetyl-2-methyl-4-heptafluoroisopropylaniline is obtained. S6: N-acetyl-2-methyl-4-heptafluoroisopropylaniline was added to 37% concentrated hydrochloric acid and an appropriate amount of methanol solution was added. The mixture was refluxed at 100-105℃ for 4-8 hours and purified to obtain 2-methyl-4-heptafluoroisopropylaniline.

2. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 1, characterized in that, The titration channel (001) includes multiple titration flow pipes (1) and multiple temporary reaction cylinders (2). The output end of the first titration flow pipe (1) is connected to the side wall of the first temporary reaction cylinder (2) near the top. The input end of the second titration flow pipe (1) is connected to the bottom of the first temporary reaction cylinder (2), and the output end is connected to the side wall of the second temporary reaction cylinder (2) near the top. In this way, 3-5 titration flow pipes (1) and temporary reaction cylinders (2) are connected in sequence. The nitrated mixed acid includes 65% nitric acid and 98% sulfuric acid. A titration port (11) for the nitrated mixed acid is set at the initial end of each titration flow pipe (1). Starting from the first titration flow pipe (1), the proportion of nitric acid in the nitrated mixed acid titrated in the subsequent titration flow pipes (1) decreases step by step. The ratio of 65% nitric acid and 98% sulfuric acid titrated at the position of the first titration flow pipe (1) is 1:4-5.

3. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 2, characterized in that, The reaction liquid in the last temporary reaction cylinder (2) flows into the water washing tank and is simultaneously discharged into the water washing tank for washing. When the water washing tank is almost full, no more liquid is discharged. After standing still, the lower organic phase is discharged. The reaction liquid in the last temporary reaction cylinder (2) will flow into the next water washing tank for washing. This process is repeated continuously. The discharged organic phase is discharged into an organic phase washing tank. 5% NaHCO3 is added to the organic phase washing tank to wash until it is weakly alkaline / neutral. It is then washed once with saturated brine to separate the lower organic phase. The organic phase is then dried with anhydrous Na2SO4 and filtered to obtain anhydrous organic phase.

4. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 1, characterized in that, The mixing channel (002) includes multiple square mixing channels (3), an exhaust pipe (33) and a condenser return pipe (4). The multiple square mixing channels (3) are connected in sequence and set down step by step. Each square mixing channel (3) has an upward exhaust pipe (33) at the top of the output end. The exhaust end of the exhaust pipe (33) is connected to the bottom side wall of the condenser. The bottom return pipe (41) of the condenser (4) is inserted downward into the input end of the next square mixing channel (3). After the 2-nitro-4-bromotoluene solution is discharged, the ammonium formate solution is dripped in by inflow or by multiple drip heads (31), and a Pd / C solution dripping tube (32) is set at a distance behind the ammonium formate solution dripping position.

5. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 1, characterized in that, The inflation channel (003) includes multiple thick cylinders (5) and multiple Z-shaped pipes (7). Each thick cylinder (5) is placed horizontally. The two ends of the thick cylinder (5) are respectively provided with an inlet and an outlet near the bottom and the top. The multiple thick cylinders (5) are connected by a Z-shaped pipe (7) and the outlet at the top of the previous thick cylinder (5) is connected to the inlet at the bottom of the next thick cylinder (5). Each of the Z-shaped pipes (7) is provided with a hydrogen branch pipe (71) near the liquid inlet. The hydrogen branch pipe (71) is used to discharge hydrogen into the Z-shaped pipe (7). The amount of hydrogen discharged into the Z-shaped pipe (7) by the hydrogen branch pipe (71) decreases step by step from the first to the last. The first coarse cylinder (5) is provided with a catalyst connector (61) on the reaction liquid drain pipe (6) connected to the liquid inlet. The Pd / C solution is discharged into the first coarse cylinder (5) through the catalyst connector (61). The reaction liquid drain pipe (6) is also provided with an initial hydrogen branch pipe (62).

6. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 1, characterized in that, The acetylation channel comprises multiple acylated square tubes arranged in a descending sequence. Each acylated square tube has an inlet and an outlet near the top and bottom, respectively. Adjacent acylated square tubes are connected by pipes to the outlet and inlet. Each section of the acylated square tube has an acetic anhydride burette at the top near the inlet.

7. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 6, characterized in that, In step S4, multiple parallel processing tanks are required for each step, including ice-water precipitation, filtration and washing, and ethanol / water recrystallization. This ensures that when the reaction solution continuously discharged from the acetylation channel enters the ice-water precipitation tank, the reaction solution in one tank can be transferred to another empty tank in a timely manner when the reaction solution in one tank is full.

8. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 7, characterized in that, The number of directional reaction tanks is matched with the number of parallel processing tanks, that is, the raw materials after recrystallization of ethanol / water in one tank are discharged into one directional reaction tank for directional reaction. Step S5, water washing for desalination, iodine removal and decolorization, and recrystallization, are also multiple parallel operations. The reaction solution after the reaction in each of the directional reaction tanks is subjected to water washing for desalination, iodine removal and decolorization, and recrystallization once.

9. The process for the directed fluoroalkylation synthesis of 2-methyl-4-heptafluoroisopropylaniline according to claim 8, characterized in that, Step S6 involves configuring multiple deacylation reaction reflux tanks. The N-acetyl-2-methyl-4-heptafluoroisopropylaniline produced after the reaction solution in each of the directional reaction tanks is washed with water to remove salt, remove iodine, decolorize, and recrystallize is added to a deacylation reaction reflux tank for reaction. The purification of the reaction solution after each deacylation reaction in the reflux tank is an independent step, and the purification steps are as follows:

1. Alkalize the reaction solution to pH 9-10 with concentrated ammonia / 50% NaOH, and slowly add it under ice bath; 2. Extract twice with dichloromethane / ethyl acetate; 3. Wash once with saturated brine.

4. Dry with anhydrous Na2SO4 and filter; 5. Rotary distillation and vacuum distillation.

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